Metabolic and chromatin reprogramming of hematopoietic stem cells (HSC) during day-night oscillations and aging

 

Humans have enormous demands for blood production. Alterations in the functioning of the human blood system lie at the heart of many diseases, including cancer, infections, and auto-immune disorders. With age, human blood production changes and immune function is decreased. There is a need to improve our understanding of how our blood system develops from the rare hematopoietic stem cells (HSC) that originate all blood cells, and how aging disrupts this process. This information is critical to develop new therapies against many diseases that originate from abnormal immune cell functioning and to potentially alleviate and/or reverse accelerated decline in HSC function.

Previous studies have shown that melatonin is critical to the day/night oscillation pattern that controls the switch HSCs make between the generation of mature blood cells and their replenishment. They also show that sphingolipids govern HSC function and the generation of mature blood cells. Melatonin and sphingolipids are therefore linked, and their levels change with age. This project will use state-of-the-art assays to study normal human blood cells as well as genetically engineered mice to investigate whether these molecules are behind the age-related decline in HSC function.

The project was selected for funding through the fifth research competition of the Joint Canada-Israel Health Research Program. This initiative is a partnership between IDRC, the Canadian Institutes of Health Research, the Israel Science Foundation, and the Azrieli Foundation.